The BCL-2 Family: A Balance Between Pro- and Anti-apoptotic Protein Expression

The BCL-2 family of proteins and its role in apoptosis

The BCL-2 family of proteins is known as an important gatekeeper to the apoptotic response. This group of structurally related proteins comprises pro-apoptotic and anti-apoptotic members (Figure 2.1) that interact with one another.

Short sequences of amino acids common to BCL-2 and other members of this protein family are known as BCL-2 homology (BH) motifs. At least 1 BH motif is contained in each of the BCL-2 family members. These motifs, in part, contribute to the function of each member.5

The BCL-2 family members can be classified into 3 functional groups: anti-apoptotic proteins such as BCL-2, pro-apoptotic effectors, and pro-apoptotic activators (Figure 2.1). Preclinical data suggest that activators, which contain only a single BH3 motif, are important mediators in the cellular response to stresses such as DNA damage.6

Effectors are those BCL-2 proteins closely associated with the mitochondrial membrane, and when stimulated by BH3-only activators, promote the formation of pores in the mitochondrial membrane, initiating the apoptotic program.7,8

Figure 2.1 The BCL-2 family5,6

BCL-2 family

Apoptosis-promoting effects from both effectors and activators are inhibited by direct interaction with anti-apoptotic BCL-2 family members.9 In preclinical models, BCL-2 binds and sequesters BH3-only activators and prevents them from interacting with the pore-forming effectors. Likewise, BCL-2 can directly influence effectors to prevent mitochondrial pore formation (Figure 2.2). The dynamic balance that occurs between anti-apoptotic members, such as BCL-2, and pro-apoptotic members helps determine whether the cell initiates apoptosis.5,7

Figure 2.2 Functional role of BCL-25,7

BCL-2 pathway of apoptosis inhibition